The invention relates to a novel stable pharmaceutical preparation comprising levothyroxine sodium, potassium iodide, microcrystalline cellulose and binding agent, which is free of antioxidants or further auxiliaries.
Auxiliaries are substances which prevent formation of iodine, e.g. potassium hydroxide.
A thyroxine preparation stabilized with thiosulfate as an antioxidant is described in DE 195 41 128.
Another known thyroxine-containing commercial preparation Thyreocomb(copyright) N (Red List 1998, 74015) contains the auxiliary potassium hydroxide, which drives the comproportionation reaction of iodide and iodate to iodine to the starting material side. In this manner, production of iodine is suppressed.
A preparation comprising levothyroxine sodium and potassium iodide for the stabilization of the active compound levothyroxine sodium is disclosed in U.S. Pat. No. 5,635,209. For a low dose, the amount of potassium iodide needed for the stabilization of levothyroxine sodium is given in a ratio of 4:1, e.g. 25 xcexcg of levothyroxine sodium and 100 xcexcg of potassium iodide. For high doses, the ratio is described as 1.5:1, e.g. 300-450 xcexcg of potassium iodide for 300 xcexcg of levothyroxine sodium. 300 xcexcg of potassium iodide were needed for the stabilization of 100 xcexcg of levothyroxine sodium.
The active compound levothyroxine sodium (=levothyroxine-Na=LT4) is sensitive to light, heat and oxygen. On account of these known stability problems, pharmaceutical preparations are therefore overdosed by up to 20%.
If, in addition to the active compound levothyroxine-Na in a pharmaceutical preparation, iodide is additionally contained, this pharmaceutical preparation becomes discoloured on storage, since the anion iodide in potassium iodide can be oxidized to iodine or can comproportionate with potassium iodate to give iodine. Furthermore, the demands on the in-vitro release for levothyroxine-Na tablets have been increased. The draft monograph of the Pharmacopeial Forum (Pharm. Preview, 1995, 21, 1459-1461) intends, in addition to the valid test 1 (phosphate buffer pH 7.4, in 80 minutes  greater than 55%), to approve the test 2 (water in 45 minutes  greater than 70%).
The invention was based on the object of making available novel medicaments in the form of pharmaceutical preparations which have better properties than known medicaments which can be used for the same purposes.
This object was achieved by the discovery of the novel preparation.
The novel preparation according to the invention essentially shows no discolouration and has an improved stability. It can be used as a thyroid hormone combination preparation, owing to the high content of iodide as a second active compound, in euthyroid iodine deficiency goitre and/or in relapse prophylaxis after resection of an iodine deficiency goitre.
The active compound iodide can be contained as an anion only in the presence of a stabilizing cation, e.g. potassium (+), and thus as a salt in a pharmaceutical preparation. 130 xcexcg of potassium iodide correspond to 100 xcexcg of iodide.
Discolouration of the preparation according to the invention is avoided, since formation of free iodine is prevented.
This novel preparation furthermore has a very good release of active compound in vitro.
The invention preferably relates to a pharmaceutical preparation as described, characterized in that it contain 5 to 400 xcexcg, of levothyroxine 300 xcexcg, in particular 50 to 200 xcexcg, of levothyroxine sodium and 5 to 400 xcexcg, preferably 10 to 300 xcexcg, in particular 25 to 200 xcexcg, of potassium iodide.
The invention furthermore preferably relates to a pharmaceutical preparation as described, characterized in that it contains levothyroxine sodium in micronized form having a particle size of between 5 and 25 xcexcm (to 95%), particularly preferably having a particle size of between 5 and 15 xcexcm (to 95%).
The invention furthermore preferably relates to a pharmaceutical preparation as described, characterized in that it contains a hydroxypropyl-methylcellulose and/or gelatine as a binding agent.
A pharmaceutical preparation is particularly preferably described, characterized in that it is a solid preparation in the form of tablets.
Particularly preferred embodiments contain 50, 75 or 100 xcexcg of levothyroxine sodium and 100 xcexcg each of iodide, 100 xcexcg of iodide corresponding to an amount of 130 xcexcg of potassium iodide. A very particularly preferred embodiment contains 100 xcexcg of levothyroxine sodium and 100 xcexcg of iodide.
On account of the known instability of levothyroxine-Na, this active compound is overdosed to 5% in the formulations.
The preparation according to the invention has a surprising stability when hydroxypropylmethyl-cellulose and/or gelatine is used as a binding agent. At the same time, formation of iodine is surprisingly suppressed without admixture of antioxidants or further auxiliaries being necessary.
The data of the stability investigations are indicated in Tables I and II as exemplified by batches 005204 (13/97) and 004609 (3/96). Based on the results, it can be seen that the tablets according to the invention which contain levothyroxine sodium (100 xcexcg) and iodide (100 xcexcg) are stable for at least 2 years if they are stored at temperatures below 30xc2x0 C. Likewise, no brown colouration of the pharmaceutical preparation is observed in this period, i.e. no formation of iodine.
Furthermore, the release of the active compound levothyroxine sodium is favoured if the active compound is employed in micronized form. Levothyroxine sodium is customarily soluble with great difficulty both in water and in ethanol. With a particle size of between 5 and 25 xcexcm (to 95%), particularly preferably between 5 and 15 xcexcm, however, a release of the active compound which corresponds to both test systems takes place (Tables I and II).
The analytical data are determined according to customary and known methods.
The invention also relates to a process for the production of a pharmaceutical preparation comprising levothyroxine sodium and potassium iodide, characterized in that levothyroxine sodium and potassium iodide, which are present in suspended form in aqueous hydroxypropylmethylcellulose and/or gelatine solution, are sprayed onto the microcrystalline cellulose in a fluidized bed granulation, then a disintegrating agent and lubricant are admixed and the mixture is compressed to give tablets.
Hydroxypropylmethylcellulose and potassium iodide are dissolved in water and levothyroxine sodium is suspended in water at temperatures between 5 and 40xc2x0 C., preferably between 10 and 35xc2x0 C., particularly preferably between 15 and 30xc2x0 C.
The temperature during the granulation is between 60 and 80xc2x0 C., preferably between 65 and 75xc2x0 C., at the inlet and between 10 and 50xc2x0 C., preferably between 20 and 40xc2x0 C., at the outlet. The spray pressure in the process according to the invention is between 3 and 5 bar.
The invention further relates to a process as described, characterized in that the disintegrating agent used is croscarmellose sodium and the lubricant used is magnesium stearate.
Further excipients or additives can be added, such as, for example, binding agents, colourants, lubricants, sweeteners and/or aromatic substances.
Preferred glidants or lubricants are, for example, talc, starch, magnesium stearate and calcium stearate, boric acid, paraffin, cocoa butter, macrogol, leucine or sodium benzoate; magnesium stearate is very particularly preferred.
The preparation according to the invention can be prepared without the use of organic solvents.